P1642: CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL ARE ASSOCIATED WITH INCREASED NETOSIS IN PATIENTS WITH CARDIOVASCULAR EVENTS
Authors: Severine Marti, Melody Dufossee, Sylvie Colomer, Sami Fawaz, Geoffrey Garcia, Yann Pucheu, Chloe James, Thierry Couffinhal, Olivier Mansier
Journal: HemaSphere (2023)

Topic: 34. Thrombosis and vascular biology - Biology & Translational Research Background: Clonal hematopoiesis of indeterminate potential (CHIP) result from the acquisition during aging of mutations in hematopoietic stem cells, in the absence of any criteria for hematological malignancy. CHIP have been associated with increased mortality, particularly related to the occurrence of cardiovascular events (CVE). Currently, most studies have focused on the role of mutated monocytes/macrophages whose pro-inflammatory properties are thought to be responsible for the cardiovascular damage associated with CHIP. However, these mutations are also found in other cell types, including neutrophils, which are the most numerous leukocytes in humans. Neutrophils are able to infiltrate atherosclerotic plaques and to participate in thrombo-inflammatory phenomena, in particular via the emission of Neutrophil Extracellular Traps (NETs). Aims: The aim of this study was to decipher if neutrophils represent an actor in the pathophysiology of CVE associated with CHIP through the emission of NETs. Methods: In this work, we studied 81 patients from the CHAth study (NCT04581057, IRDCB 2019-A02902-05). These patients have benefited from a blood sample 2-7 months after a first myocardial infarction (MI) (median age 81.7 years, 72% men). The presence of CHIP was defined by the detection of at least 1 mutation with a variant allele frequency (VAF) ≥2%. Basal inflammation was assessed by plasmatic hsCRP and IL1β levels. Atheromatous burden was assessed at the carotid (atheromatous volume measured by 3D ultrasound and detection of a >50% carotid stenosis) and coronary (presence of multi-truncal lesions) levels. We assessed the levels of 2 plasmatic NETs markers by ELISA: myeloperoxidase-DNA complex (MPO-DNA) and citrullinated histone H3 (H3-Cit). Finally, we looked for an association between the existence of CHIP and MPO-DNA and H3-Cit levels, as well as an association between CHIP, NETs levels, and basal inflammation, atheromatous burden, and the occurrence of complications at 1 year post-MI. Results: Fifty-four percent of patients were CHIP carriers. The 2 most frequently mutated genes were DNMT3A (50%) and TET2 (39%). The presence of CHIP was associated with a significant increase in MPO-DNA (3.1 vs 2.5%, p=0.004) and H3-Cit (0.19 vs 0.15, p=0.038) plasmatic levels. However, neither the presence of CHIP nor increased biomarkers of NETs (either alone or in combination) were associated with increased systemic inflammation, coronary or carotid atheromatous burden, or incidence of complications. Summary/Conclusion: This study is the first to show that CHIP is associated with increased plasmatic levels of NETs. Confirmation of these results in animal models is currently underway. However, in the context of a recent MI, CHIP and NETs do not appear to be associated with systemic inflammation, increased development of atherosclerosis, or increased risk of post-MI complications. Analysis of a larger number of patients, including patients without prior CVE, is needed to confirm these findings and to determine whether or not NETs are involved in the occurrence of CVE in the presence of CHIP. Keywords: Neutrophil, Atherosclerosis, CHIP, Myocardial infarction